Application of Conformation Design in Acyclic Stereoselection: Total Synthesis of Borrelidin as the Crystalline Benzene Solvate

Article abstract of DOI:10.1021/ja030139k

The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating C-methyl groups with a C₄-C₁₀ syn/syn/anti orientation was elaborated by a new method of iterative cuprate additions to acyclic α,β-unsaturated esters relying on two consequtive 1,3-inductions and starting with D-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer by application of the Still-Gennari olefination protocol. The γ-hydroxycyclopentane carboxylic acid subunit was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing on 1,2-induction in an acyclic α,β-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated by ¹H NMR homodecoupling studies.

Full text of DOI:10.1021/ja030139k

Published on Web 10/16/2003
Application of Conformation Design in Acyclic
Stereoselection: Total Synthesis of Borrelidin as the
Crystalline Benzene Solvate
Stephen Hanessian,* Yang Yang, Simon Giroux, Vincent Mascitti, Jianguo Ma, and
Franck Raeppel
Contribution from the Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128,
Station Centre-Ville Montre´al, ProVince of Quebec H3C 3J7, Canada
Received February 26, 2003; Revised Manuscript Received August 6, 2003; E-mail: stephen.hanessian@umontreal.ca
Abstract: The total synthesis of (-)-borrelidin (treponemycin), a structurally distinct 18-membered macrolide
antibiotic, has been achieved. It was isolated as the crystalline benzene solvate, and its structure was
confirmed by a single-crystal X-ray analysis. The deoxypropionate subunit consisting of four alternating
C-methyl groups with a C4-C10 syn/syn/anti orientation was elaborated by a new method of iterative cuprate
additions to acyclic R,â-unsaturated esters relying on two consequtive 1,3-inductions and starting with
D-glyceraldehyde as the chiral progenitor. The unique Z/E cyanodiene unit was obtained as a single isomer
by application of the Still-Gennari olefination protocol. The γ-hydroxycyclopentane carboxylic acid subunit
was prepared from L-malic acid utilizing a sequential introduction of C-vinyl and C-allyl groups, capitalizing
on 1,2-induction in an acyclic R,â-unsaturated ester and carbocyclization by a Grubbs ring closure metathesis
reaction. The prevalence of 1,3-syn-disposed deoxypropionate triads in the cuprate additions is rationalized
on the basis of minimized syn-pentane interactions in the transition states. A virtual diamond lattice was
used as a visual tool to portray the low-energy conformations of the acyclic substrates, and corroborated
1
by H NMR homodecoupling studies.
Borrelidin (treponemycin) is a structurally distinct, atypical
macrolide antibiotic produced by a variety of Streptomyces.1
In addition to its long-known inhibitory effect against experi-
mental infections caused by Borrelia, the spirochete of relapsing
fever,2 it also exhibits a diverse spectrum of biological activities.3
The inhibition of cyclin-dependent kinase of Saccharomyces
cereVisiae4 and the potent antiangiogenesis activity5 in the rat
aorta have attracted renewed attention to this structurally unique,
albeit toxic, nitrile-containing natural product.6 The structure
of borrelidin (1, Figure 1), was elegantly determined by chemical
degradation,7 and its absolute configuration was deduced by
X-ray crystallography of a (S)-2-methylbutanol solvate.8 Morken
and co-workers9 have recently reported the first total synthesis
of borrelidin utilizing enantioselective asymmetric methods
of subunit construction and assembly. The synthesis of indi-
vidual deoxypropionate subunits has been the subject of two
reports,10,11 relying on a Sharpless asymmetric epoxidation12 and
a Myers13 enolate alkylation as key reactions, respectively.
Borrelidin (1) displays structural and functional features that
distinguish it among macrolides and related natural products.14
Thus, the C1-C11 substructure encompasses four 1,3-alternating
C-methyl groups as part of deoxypropionate segments with a
distinctive syn/syn/anti relationship. Moreover, the Z/E cyano-
diene unit at C13-C16 and the γ-hydroxy â-branched cyclopen-
tane carboxylic acid unit have not been previously encountered
in other natural products.
We describe herein the stereocontrolled total synthesis of crys-
talline (-)-borrelidin, isolated and characterized as its benzene
solvate for the first time. Antithetic disconnections reveal acyclic
and carbocyclic subunits that originate from D-glyceraldehyde
and L-malic acid, respectively, as chiral progenitors, relying on
a series of 1,2- and 1,3-inductions (Figure 1). The assembly
plan would involve the coupling of a sulfone anion, prepared
* Corresponding author: phone (514) 343-6738; fax (514) 343-5728.
(1) Borrelidin: (a) Berger, J.; Jampolsky, L. M.; Goldberg, M. W. Arch.
Biochem. 1949, 22, 476. (b) Lumb, M.; Macey, P. E.; Spyvee, J.;
Whitmarsh, J. M.; Wright, R. D. Nature 1965, 206, 263. Treponemycin:
(c) Maehr, H.; Evans, R. H. J. Antibiot. 1987, 40, 1455; J. Antibiot. 1988,
C-1. (d) Singh, S. K.; Gurusiddaiah, S.; Whalen, J. W. Antimicrob. Agents
Chemother. 1985, 27, 239.
(2) Buck, M.; Farr, A. C.; Schnitzer, R. J. Trans. N.Y. Acad. Sci., Ser. 2 1949,
11, 207.
(3) For reports of an antiviral, insecticidal, herbicidal activity and inhibition
of eukaryotic and prokaryotic threonyl-tRNA, see references in Supporting
Information.
(4) Tsuchiya, E.; Yukawo, M.; Miyakawo, T.; Kinura, K.; Takahashi, H. J.
Antibiot. 2001, 54, 84.
(5) (a) Wakabayashi, T.; Kageyama, R.; Naruse, N.; Tsukahara, N.; Funahashi,
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(14) See for example: (a) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.;
Baran, P. Angew. Chem., Int. Ed. 2000, 39, 44. (b) Corey, E. J.; Cheng,
X.-N. The Logic of Chemical Synthesis; J. Wiley & Sons: New York, 1989.
9
13784
J. AM. CHEM. SOC. 2003, 125, 13784-13792
10.1021/ja030139k CCC: $25.00 © 2003 American Chemical Society

Total Synthesis of (−)-Borrelidin
A R T I C L E S
Figure 1. Borrelidin and its chiral progenitors.
from the cyclopentane carboxylic acid subunit A, to an acyclic
cyanodiene aldehyde B, followed by cyclization to the 18-
membered macrolactone and further elaboration to (-)-borre-
lidin.
syn-disposed 2,4-dimethylpentane motifs. The occurrence of
deoxypropionate subunits in natural products has instigated
many methods for their stereocontrolled synthesis.13,28 In some
cases, these methods have been utilized in an iterative manner
to prepare acyclic motifs containing 2,4-dimethyl- and 2,4,6-
C1-C13 Substructure. Our first objective was to explore the
prospects of a new synthesis of syn-disposed deoxypropionate
subunits that could be applicable to borrelidin and other natural
products. It is of interest that in the majority of natural products
containing alternating 1,3-dimethyl groups on acyclic chains,
their dispositions are invariably all-syn. Among those with two
syn-disposed deoxypropionate units (two stereotriads)15 for
example are pectinatone,16 lardolure,17 TMC-151,18 siphonar-
ienolone,19 and siphonarienal.20 Doliculide21 and borrelidin (1)
are examples of macrolides that contain a syn-disposed 2,4,6-
trimethylheptane motif in their macrolactone framework. Iono-
mycin,22 zaragozic acid A,23 rapamycin,24 rakicidin C,25 and
several macrolides26 and ionophores27 contain substructures with
13,16,28a,b
trimethyldeoxypropionate subunits.
We have previously reported on the stereocontrolled synthesis
of polypropionate subunits by an iterative protocol, whereby
an enantiopure γ-alkoxy-R,â-unsaturated ester was subjected
to a conjugate addition of lithium dimethylcuprate (Gilman
cuprate), followed by hydroxylation of the corresponding
potassium enolate.29 Homologation to a new γ-alkoxy enoate,
reiteration of the conjugate addition, and enolate hydroxylation
afforded propionate triads of defined stereochemistry in a
growing acyclic chain. This protocol of acyclic stereoselection
relying on a series of sequential 1,2-inductions was successfully
(23) Zaragozic acid A isolation: (a) Dawson, J. M.; Farthing, J. E.; Mashall, P.
S.; Middleton, R. F.; O’Neill, M. J.; Shuttleworth, A.; Stylli, C.; Tait, R.
M.; Taylor, P. M.; Widlman, H. G.; Buss, A. D.; Langley, D.; Hayes, M.
V. J. Antibiot. 1992, 45, 639. Zaragozic acid A synthesis: (b) Nicolaou,
K. C.; Nadin, A.; Leresche, J. E.; Yue, E. W.; La Greca, S. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2190. (c) Caron, S.; Stoermer, D.; Mapp, A. K.;
Heathcock, C. H. J. Org. Chem. 1996, 61, 9126. (d) Tomooka, K.; Kikuchi,
M.; Igawa, K.; Suzuki, M.; Keong, P.-H.; Nakai, T. Angew. Chem., Int.
Ed. 2000, 39, 4502.
(24) Rapamycin isolation: (a) Ve´zina, C.; Kudelska, A.; Sehgal, S. N. J.
Antiobiot. 1975, 28, 721. Rapamycin synthesis: (b) Nicolaou, K. C.;
Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem.
Soc. 1993, 115, 4419. (c) Romo, D.; Meyer, S. D.; Johnson, D. D.;
Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 7906. (d) Hayward, C. M.;
Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 9345. (e)
Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy,
J. W.; Maleczka, R. J. Am. Chem. Soc. 1995, 117, 5407.
(25) Hu, J.-F.; Wunderlich, D.; Satter, I.; Feng, X.-Z.; Grabley, S.; Thiericke,
R. Eur. J. Org. Chem. 2000, 3356.
(26) For reviews, see (a) Paterson, I.; Mansuri, M. M. Tetrahedron, 1985, 41,
3569. (b) Norcross, R. D.; Paterson, I. Chem. ReV. 1995, 95, 2041. (c)
Ohmura, S. Macrolide Antibiotics: Chemistry, Biology, and Practice, 2nd
ed.; Academic Press: New York, 2002.
(27) For reviews, see (a) Yonemitsu, O.; Horita, K. In Recent Progress in the
Chemical Synthesis of Antibiotics; Lukacs, G., Ohno, M., Eds.; Springer-
Verlag: New York, 1990; p 448. (c) Perron, F.; Albizzati, K. F. Chem.
ReV. 1989, 89, 1617. (c) Boivin, T. L. B. Tetrahedron, 1987, 43, 3309. (d)
Polyether Antibiotics: Naturally Occurring Acid Ionophores; Westley, J.
W., Ed.; Marcel Dekker: New York, 1982; Vol. 1, 2. (e) Wierenga, W. In
The Total Synthesis of Natural Products; ApSimon, J., Ed.; Wiley-
Interscience: New York, 1981; Vol. 4, p 263.
(15) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987, 26, 489.
(16) Pectinatone isolation: (a) Biskupiak, J. E.; Ireland, C. M. Tetrahedron Lett.
1983, 24, 3055. Pectinatone structure: (b) Norte´, M.; Cataldo, F.; Gonzalez,
A. G.; Rodriguez, M. L.; Ruiz-Perez, C. Tetrahedron 1990, 46, 1669.
Pectinatone synthesis: (c) Birkbeck, A. A.; Enders, D. Tetrahedron Lett.
1998, 39, 7823.
(17) Lardolure stereochemistry and synthesis: (a) Mori, K.; Kuwahara, S.
Tetrahedron 1986, 42, 5545. Lardolure synthesis: (b) Mori, K.; Kuwahara,
S. Tetrahedron 1986, 42, 5539. (c) Kaino, M.; Naruse, Y.; Ishihara, K.;
Yamamoto, H. J. Org. Chem. 1990, 55, 5814. (d) Morr, M.; Proppe, C.;
Wray, V. Liebigs Ann. 1995, 2001.
(18) TMC-151 structure: Kohno, J.; Nishio, M.; Sakurai, M.; Kawano, K.;
Hajime, H.; Kameda, N.; Kishi, N.; Yamashita, T.; Okuda, T.; Komatsubara,
S. Tetrahedron 1999, 55, 7771.
(19) Siphonarienolone isolation and structure: (a) Norte´, M.; Cataldo, F.;
Gonzalez, A. G. Tetrahedron. Lett. 1988, 29, 2879. Siphonarienolone
synthesis: (b) Calter, M. A.; Liao, W. J. Am. Chem. Soc. 2002, 124, 13127.
(20) Siphonarienal isolation and synthesis: (a) Norte´, M.; Fernandez, J. J.;
Padilla, A. Tetrahedron Lett 1994, 35, 3413. Siphonarienal synthesis: (b)
Calter, M. A.; Liao, W.; Strauss, J. A. J. Org. Chem. 2001, 66, 7500.
(21) Doliculide structure: (a) Ishiwata, H.; Nemoto, M.; Ojika, M.; Yamada,
K. J. Org. Chem. 1994, 59, 4710. Doliculide synthesis: (b) Ishiwata, H.;
Sone, H.; Kizoshi, H.; Kaneada, K. Tetrahedron 1994, 50, 12853. (c) Ghosh,
A. K.; Liu, C. Org. Lett. 2001, 3, 635.
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9
J. AM. CHEM. SOC. VOL. 125, NO. 45, 2003 13785

A R T I C L E S
Hanessian et al.
applied to the synthesis of the eight contiguous stereogenic
centers in the polypropionate subunit of rifamycin S30 and to
the total synthesis of bafilomycin A1.31 We describe herein a
new method for the synthesis of enantiopure acyclic esters
containing the syn-4,6,8-trimethyl substitution pattern found in
the C1-C9 substructure of borrelidin (Figure 1) and its further
elaboration to the target itself.
last C-methyl group at C10 with the desired stereochemistry.
Thus, the trisubstituted ester 11, prepared from the alcohol
precursor 9 in two steps, was subjected to a variety of reduction
conditions in an effort to secure the C10 methyl group. Un-
fortunately, none of the conditions tried gave satisfactory
results.33 We then decided to attempt a regioselective opening
of the epoxide 12. Reduction of the ester 11 and treatment of
the resulting allylic alcohol with VO(acac)2 in the presence of
TBHP gave the desired epoxide as a 6:1 mixture of isomers.
On the other hand, Sharpless-Katsuki epoxidation12 led to 12
as the major product (20:1). The next challenge was to effect a
regioselective ring opening of the epoxide 12 at the tertiary site.
There are a number of examples of Lewis acid-catalyzed ring
openings of epoxy alcohols.34 Thus, use of NaCNBH3/BF3‚Et2O,
Dibal-H, or LiBH4/Ti(i-PrO)4 gave, after pivaloylation, the
desired 13, albeit with little or no selectivity. However, use of
LiBH4/BF3‚Et2O afforded 13 as a major regioisomer in a ratio
of 6:1. Protection of the hydroxyl group in 13 as a TBS ether,
hydrogenolysis to remove the BOM ether, mesylation of the
resulting alcohol, and selective cleavage of the TBDPS ether
with Bu4NF led to concomitant formation of the inverted
epoxide 14. Cleavage of the epoxide with vinylmagnesiocuprate
and protection of the resulting alcohol as the TBS ether gave
15, which was deesterified to the primary alcohol. Thus, the
C1-C13 substructure of borrelidin was secured in a stereocon-
trolled manner by two sequential conjugated additions of lithium
dimethylcuprate to R,â-unsaturated esters relying on syn-
selective 1,3-induction.
Highly selective conjugate addition of lithium dimethylcuprate
in the presence of TMSCl32 to the readily available enoate 2
gave the adduct 3 as previously reported.29a Reduction of the
methyl ester, followed by Swern oxidation and homologation,
afforded the tert-butyl enoate 4 in excellent overall yield
(Scheme 1). Cuprate addition to 4 led to a mixture of 5 and its
anti isomer (not shown) in a ratio of 4:1 in favor of the desired
syn isomer. Reduction to the respective alcohols afforded 6,
which was separated from the minor anti isomer and then
homologated to the enoate 7. A third cuprate addition afforded
the C3-C7 syn/syn adduct 8 as the major product in 88% yield
(syn/syn:anti/syn > 10:1 by 600 MHz 1H NMR analysis of the
homologated enoate). Its configurational identity was established
by conversion to a known enantiopure product (see later).
Although a fourth cuprate addition to the homologated enoate
10 proceeded in excellent yield, the resulting adduct harboring
a terminal anti triad as required for C10 in borrelidin was
obtained as the minor isomer compared to the seemingly favored
all-syn configuration (syn/anti 2:1 for the last cuprate adduct).
Therefore, a different approach was pursued to introduce the
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Chem., Int. Ed. Engl. 1994, 33, 2184. Auxiliary-mediated Cope rearrange-
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Z/E Cyanodiene Substructure. As previously mentioned,
the Z/E diene unit in borrelidin is unique among natural products
that contain a nitrile group.6 Although cyanoolefins have been
prepared from phosphorus-based reagents,35 the necessity to
have a Z-geometry presented an opportunity to apply the Still-
Gennari olefination conditions.36 Oxidation of the alcohol
obtained from 15 to the corresponding aldehyde and treatment
37
with TMSCN in the presence of AlCl3 afforded the cyano-
hydrin 16 as a mixture of isomers (Scheme 1). Although several
attempts to oxidize 16 to the corresponding cyanoketone (MnO2,
PCC, Swern) led to decomposition, oxidation was successfully
achieved in excellent yield with the Dess-Martin periodinane
reagent.38 Olefination under the Still-Gennari conditions took
place to give the Z-cyanomethoxycarbonylmethylene product
17 as a single isomer as evidenced by 1H and 13C NMR.
Subsequent reduction to the alcohol 18 via the mixed anhydride
and oxidation with the Dess-Martin reagent afforded the
aldehyde intermediate 19.
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ZnCl2. L-Selectride and superhydride resulted in 1,2-reduction of the ester.
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(38) (a) Dess, D. B.; Martin, J. C.; J. Org. Chem. 1983, 48, 4155. (b) Dess, D.
B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
9
13786 J. AM. CHEM. SOC. VOL. 125, NO. 45, 2003

Total Synthesis of (−)-Borrelidin
A R T I C L E S
Scheme 1 a
t
a Reagents and conditions: (a) Dibal-H, CH2Cl2 (80%); (b) (COCl)2, DMSO, NEt3, CH2Cl2, -78 °C (96%); (c) PPh3CHCO2 Bu, CH2Cl2 (91%); (d)
MeLi‚LiBr, CuI, TMSCl, THF, -78 °C (93%, 4:1 syn-6/anti-6a); repeat a (82%); repeat b (88%); repeat c (90%); repeat d (88%) [syn/syn/syn > 90% by
chiral GC analysis of a derivative]; repeat a (92%); repeat b (77%); (e) MeLi‚LiBr, THF, -78 °C; repeat b (80% for two steps); (f) LiHMDS,
t
(MeO)2P(O)CH2CO2Me, THF, reflux, 12 h (88% 9:1 E/Z); repeat a (96%); (g) (+)-diethyl tartrate, Ti(iPrO)4, BuOOH, CH2Cl2, -20 °C (86%, 20:1); (h)
LiBH4, BF3‚OEt2, THF (71%, 6:1); (i) PivCl, NEt3, DMAP, CH2Cl2 (91%); (j) TBSOTf, 2,6-lutidine, CH2Cl2 (90%); (k) H2, Pd/C 10%, MeOH (80%); (l)
MsCl, NEt3, CH2Cl2 (82%); (m) TBAF, THF; (n) K2CO3, MeOH (88% for two steps); (o) vinylMgBr, CuI, THF, -78 °C (82%); repeat j (91%); repeat a
(98%); (p) Dess-Martin periodinane, CH2Cl2; (q) TMSCN, AlCl3, CH2Cl2, then PPTS, MeOH (92% for three steps); repeat p; (r) KHMDS, 18-crown-6,
(CF3CH2O)2P(O)CH2CO2Me, THF, -35 °C (70% for two steps); (s) LiOH, THF/MeOH/H2O (3:1:1); (t) EtOCOCl, NEt3,THF, then NaBH4, MeOH (51%
for two steps); repeat p (90%).
Cyclopentane Carboxylic Acid Substructure. Our strategy
for the synthesis of the cyclopentane carboxylic acid with its
γ-hydroxy appendage also relied on acyclic precursors. Thus,
L-malic acid was easily converted to the chain-extended enoate
20, which was subjected to conjugate addition with vinylmag-
nesiocuprate to afford the C-vinyl adduct 21 as the major isomer
(5.5:1) (Scheme 2).29b,39 Alkylation of the potassium enolate
with allyl iodide gave the syn-allylated adduct 22 as previously
reported for related vicinal 1,2-C-alkylations.29b Carbocyclization
by the venerable Grubbs ring closure metathesis40 led to 23 in
excellent yield. Hydrogenation and further manipulations of the
hydroxyl groups by well-precedented methodology41 followed
by separation of the minor isomer afforded the enantiopure
sulfone intermediate 24 as the coupling partner to the previously
obtained aldehyde 19.
Assembly of Units and Completion of Synthesis. With the
two subunits 19 and 24 in hand, we proceeded with their
coupling under the conditions of the Julia reaction42 as modified
by Kocienski and co-workers (Scheme 3).41 Thus, addition of
the aldehyde 19 to a solution of the phenyltetrazole sulfone 24,
previously treated with NaHMDS and 15-crown-5 in THF at
-78 °C, afforded the desired Z/E cyanodiene 25 and its isomeric
E/E product in a ratio of 5:1, respectively. Various attempts to
improve this ratio by varying the base and solvent were not
successful.43 We next addressed the selective oxidative cleavage
of the terminal olefin. Under carefully controlled conditions of
time and temperature, it was possible to achieve clean cleavage
with OsO4 and NMO in aqueous THF. Although the isolated
yield of the aldehyde was modest (∼25%), the unreacted olefin
could be easily recycled and an overall yield of 95% could be
achieved. Evidently, the cyanodiene unit was also susceptible
to prolonged exposure to the oxidant, hence a careful monitoring
of the progress of the reaction was needed. Attempts to
(39) For examples of lithium dialkylcuprate additions to R,â-unsaturated esters
having a γ-acetal group, see (a) Nicolaou, K. C.; Pavia, M. R.; Seitz, S. P.
J. Am. Chem. Soc. 1981, 103, 1224. (b) Ziegler, F. E.; Gilligan, P. J. J.
Org. Chem. 1981, 46, 3814. (c) Roush, W. R.; Lesur, B. M. Tetrahedron
Lett. 1983, 24, 2231. (d) Larcheveque, M.; Tamagau, G.; Petit, Y. J. Chem.
Soc., Chem. Commun. 1989, 31. (e) Nemoto, H.; Ando, M.; Fukumoto, K.
Tetrahedron Lett. 1990, 31, 6205.
(40) Fu, G. C.; Grubbs, R. H. J. Am. Chem. Soc. 1992, 114, 5426.
(41) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morely, A. Synlett 1998,
26.
(42) (a) Julia, M.; Paris, J.-M., Tetrahedron Lett. 1973, 14, 4833. (b) Kocienski,
P. J.; Lythgoe, B.; Ruston, S. J. Chem. Soc., Perkin Trans. 1 1978, 829.
(43) The following conditions gave lower ratios: KHMDS/THF, -78 °C;
KHMDS/18-crown-6/THF, -78 °C; KHMDS/DME, -78 °C; LiHMDS/
THF, -78 °C; and NaHMDS/THF, -78 °C.
9
J. AM. CHEM. SOC. VOL. 125, NO. 45, 2003 13787

A R T I C L E S
Hanessian et al.
Scheme 2 a
Figure 2. Synthetic borrelidin as its benzene solvate.
molecules were located near the cyanodiene portion in the unit
cell in a 1:1 ratio.46 This new benzene solvate is the second
crystalline form of borrelidin since its initial isolation and X-ray
structure elucidation as the (S)-2-methylbutanol solvate.8
a Reagents and conditions: (a) vinylMgBr, CuI, TMSCl, THF, -78 °C,
(83%, 5.5:1 anti/syn); (b) KHMDS, THF, -78 °C, then allyl iodide (72%);
(c) Grubbs’ catalyst, CH2Cl2, rt (98%); (d) H2, Pd/C 10%, MeOH/AcOH
(4:1) (quant); (e) 1-phenyl-1H-tetrazole-5-thiol, PPh3, DIAD, THF, 0 °C
to rt (97%); (f) TESOTf, 2,6-lutidine, CH2Cl2 (85%); (g) m-CPBA,
NaHCO3, CH2Cl2, rt, 12 h (71%).
Other Synthetic Applications of the Iterative syn-Deoxy-
propionate Method. As already outlined, it was our intention
to explore the practicality of iterative conjugate addition of
Gilman cuprates to acyclic δ-methyl-R,â-unsaturated esters as
a method to access syn-deoxypropionate triads. The few reported
examples utilize chiral auxiliaries as a means of asymmetric
induction. Sakai and co-workers47 showed a modest level of
diastereoselectivity in the addition of lithium dimethylcuprate
to R,â-unsaturated monoesters of (R,R)-1,2-cyclohexanediol
prepared from R- and S-citronellal. Depending on the config-
uration of the resident C-methyl group, they obtained syn/anti
ratios of 1:1 or 3:1 in 40-42% yields. Breit and Demel48
reported conjugate addition of lithium dimethylcuprate to
enantiopure R,â-unsaturated esters already containing a predis-
posed δ-C-methyl group and an adjacent directing group. They
obtained a high preponderance of the anti-deoxypropionate
isomer as determined by NMR. Williams et al.49 described the
stereoselective synthesis of syn- and anti-1,3-dimethyl arrays
of deoxypropionates relying on the conjugate addition to
enantiopure N-enoyloxazolidinones. Oppolzer et al.50 synthe-
sized anti-deoxypropionate units relying on stereoselective
additions of an organocopper reagent already harboring a
stereogenic C-methyl group to R,â-unsaturated camphosultam
amides. To the best of our knowledge, these are the only known
examples of a single-stage addition of lithium dimethylcuprate
to δ-methyl R,â-unsaturated esters that lead to a 1,3-dimethyl
deoxypropionate triad.
Scheme 3 a
a Reagents and conditions: (a) NaHMDS, 15-crown-5, then 19, THF,
-78 °C to rt (5:1 E/Z, 66%); (b) OsO4, NMO, THF/H2O (25%, 95% after
recycling); (c) NaIO4, THF/H2O; (d) NaClO2, NaH2PO4, MeCN/H2O (74%
for two steps); (e) PPTS, MeOH/CH2Cl2 (93%); (f) 2,4,6-trichlorobenzoyl
chloride, NEt3, THF/PhMe, 40 °C (73%); (g) HF, MeCN/H2O (72%); (h)
TBAF, THF (94%).
selectively cleave the terminal olefin with ozone by using Sudan
red as an indicator44 gave intractable mixtures.
Oxidation of the aldehyde to the carboxylic acid, selective
cleavage of the TES ether, and separation of the minor E/E-
cyanodiene isomer gave pure 26. There remained to effect
macrolactonization and deprotection to obtain the intended
target. In the event, Yamaguchi lactonization
45
proceeded
The present study has shown that two consequtive 1,3-syn-
selective cuprate additions to enoates and their homologues that
contain a δ-methyl group are possible. Although only minor
amounts of the presumed C3-C7 anti/syn diastereomer could
be detected in the third cuprate addition product 8 (Scheme 1)
smoothly to afford 27 in 73% yield. The TBS ethers were
cleaved with HF in aqueous acetonitrile, and the resulting TMSE
ester was hydrolyzed with TBAF to afford crude borrelidin.
Chromatographic purification and crystallization from benzene/
hexane afforded X-ray quality crystals of borrelidin as the
benzene solvate (Figure 2), identical with an authentic sample
(mp, [R]D, LC/MS). It is interesting that the solvated benzene
1
by 13C and H NMR, we sought to obtain further evidence for
(46) See Supporting Information for details.
(47) Ogawa, T.; Suemune, H.; Sakai, K. Chem. Pharm. Bull. 1993, 41, 1652.
(48) Breit, B.; Demel, P. Tetrahedron 2000, 56, 2833.
(49) Williams, D. R.; Kissel, W. S.; Li, J. J.; Mullins, R. J. Tetrahedron Lett.
2002, 43, 3723.
(50) Oppolzer, W.; Maretti, R.; Bernardinelli, G. Tetrahedron Lett. 1986, 27,
4713.
(44) (a) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis. 1980, 807. (b)
Hanessian, S.; Ugolini, A.; Hodges, P. J.; Dube´, D. Tetrahedron Lett. 1986,
27, 2699.
(45) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem.
Soc. Jpn. 1979, 52, 1989.
9
13788 J. AM. CHEM. SOC. VOL. 125, NO. 45, 2003

Total Synthesis of (−)-Borrelidin
A R T I C L E S
Scheme 4 a
syn isomer was at higher field relative to C6 of the same isomer.
Again, the same trend was reversed in the anti isomer (Table
1, entries 1 and 2). These observations could be extended to
syn/syn and anti/syn triads harboring three alternating C-methyl
groups (Table 1, entries 3 and 4, compare C4 and C8). A similar
trend, albeit with smaller chemical shift differences between a
pair of syn and anti triads, has been observed by Breit and
Demel.48 Enoates containing 1,3-syn and anti triads can also
be distinguished from a study of characteristic chemical shift
differences between geminal methylene protons.46 Chemical shift
differences between methylene protons closest to the newly
introduced methyl group in the enoate 10 are larger in the syn/
syn compared to the anti/syn isomer (Figure 3B; compare H,I
vs H′,I′ and E,F vs E′,F′). The same trend was observed in the
case of syn-7 and its minor anti isomer.46 Thus, the chemical
shift values in the 13C and 1H spectra of deoxypropionate triads
of δ-methyl-R,â-unsaturated esters can be used as means of
relative syn and anti stereochemical assignment.53
a Reagents and conditions: (a) Dibal-H, PhMe, -78 °C (92%); (b) TsCl,
pyridine (88%); (c) MeLi, CuI, Et2O, -40 °C (100%); (d) TBAF, THF;
(e) H2 (60 psi), Pd/C, MeOH/AcOH (87% for two steps); (f) NaIO4, CH2Cl2/
H2O; (g) PPh3C(Me)CO2Et, PhMe/CH2Cl2, 80 °C (85% for two steps); (h)
Dibal-H, CH2Cl2, -78 °C (100%); (i) MnO2, hexane (94%).
its configurational identity by conversion to a known natural
product before proceeding with the synthesis of borrelidin.51
Among the marine natural products isolated from the genus
Siphonarea griseo are the metabolites siphonarienal 2920 and
siphonarienone28a that harbor syn/syn-deoxypropionate triads
(Scheme 4). Calter,19 Norte´,20 and their co-workers have reported
total syntheses of siphonarienal 29 utilizing catalytic and
noncatalytic asymmetric methods, respectively. In both methods,
the deoxypropionate motif was secured by a two-step deoxy-
genation of an initially obtained propionate triad to afford
siphonarienal. Compound 8, with the correct C3-C7-trimethyl
substitution pattern and absolute stereochemistry already in
place, was converted in five simple steps to 28 in 70% overall
yield (Scheme 4). Cleavage of the terminal diol and Wittig
olefination led to the corresponding trisubstituted ester, which
upon reduction and allylic oxidation gave siphonarienal with
physical constants identical to reported values.20
Syn-Selective Deoxypropionate Synthesis Based on Con-
formation Control. The most basic structural repetitive motif
in a polydeoxypropionate chain is a 2,4-dimethylpentane unit.
Despite its many degrees of rotational freedom, 2,4-dimethyl-
pentane can be rendered monoconformational by anchoring an
inductor group at one end of the chain, thereby orienting the
two methyl groups so as to avoid 2,4-dimethylpentane interac-
tions.54 On a macroscopic scale, this preference is manisfested
in the structure of all-syn homogeneously isotactic polypropy-
lene,55 which crystallizes in a helical conformation. Asymmetric
1,3-induction in the polymerization of methyl methacrylate was
observed by Leitereg and Cram.56 Insightful studies by R. W.
Hoffmann54a-c have shown that the calculated preferences for
extended conformations in derivatives of 1-tert-butyl-substituted
isotactic oligodeoxypropionates are in the order 2,4-dimethyl-
alkane (91% syn) > 2,4,6-trimethylalkane (76% syn) > 2,4,6,8-
tetramethylalkane (58% syn).54a For entropic reasons, the pref-
erence for conformational control favoring syn-disposed methyl
groups diminishes as 2,4-dimethylpentane units are added to
existing triads.54a,57 Nature appears to be using the same con-
formation principles to avoid syn-pentane interactions in the
In an effort to demonstrate the viability of the iterative
conjugate addition of cuprates to δ-methyl-R,â-unsaturated
enoates, we show two additional examples of 1,3-syn-selective
deoxypropionate motifs (Scheme 5). Homologation of 3029b
(>10:1 anti/anti-syn/anti) to the enoate 31, followed by cuprate
addition, afforded the C3-C5 syn isomer 32 as the preponderant
1
product (syn/anti > 7:1 by 600 MHz H NMR analysis of the
homologated enoate).46,52 Manipulation of functional groups in
32 by deoxygenation, reduction, and protection of the primary
alcohols as MOM ethers afforded the meso compound 34.52
Homologation of 32 to the corresponding enoate followed by
cuprate addition afforded 33 as the major isomer C3-C7 (syn/
(53) For a review on the 13C NMR orientation effects in acyclic systems, see
(a) Wilson W. K.; Stothers, J. B. In Topics in Stereochemistry; Eliel, E.
L., Allinger, N. L., Eds.; J. Wiley & Sons: New York; Vol. 8, pp 2-174.
See also (b) Stahl, M.; Scho¨pfer, U. J. Chem. Soc., Perkin Trans. 2 1997,
905.
(54) For an insightful discussion on conformation control of acyclic and cyclic
compounds, see (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 2000, 39,
2054. (b) Hoffmann, R. W.; Gottlich, R.; Scho¨pfer, U. Eur. J. Org. Chem.
2001, 1865. (c) Hoffmann, R. W.; Stahl, M.; Schopfer, U.; Frenking, G.
Chem. Eur. J. 1998, 4, 559. (d) Anderson, J. E. In The Chemistry of Alkanes
and Cycloalkanes; Patai, S., Rapoport, Z., Eds.; J. Wiley & Sons: New
York, 1992; pp 45-133 and cited references. (e) Yamamoto, Y.; Nemoto,
H.; Kikuchi, R.; Komatsu, H.; Suzuki, I. J. Am. Chem. Soc. 1990, 112,
8598.
(55) (a) Natta, G.; Corradini, P. J. Polym. Sci. 1959, 39, 29. (b) Pucci, S.;
Aglietto, M.; Luisi, P. L. J. Am. Chem. Soc. 1967, 89, 2787. (c) Golam,
O.; Goren, Z.; Biali, S. E. J. Am. Chem. Soc. 1990, 112, 9300. (d) Nolte,
R. J. M. Chem. Soc. ReV. 1994, 23, 11. (e) Okamoto, Y.; Nakano, T. Chem.
ReV. 1994, 94, 349. (f) Green, M M.; Park, J.-W.; Sato, T.; Teramoto, A.;
Lifson, S.; Selinger, R.; Selinger, J. V. Angew. Chem., Int. Ed. Engl. 1999,
38, 3138.
(56) Leitereg, T. J.; Cram, D. J. J. Am. Chem. Soc. 1968, 90, 4019.
(57) It is estimated that an energy gap as high as 7 kJ/mol-1 can be created
between the lowest and highest energy conformers of hydrocarbon
backbones carrying alternating 1,3-dimethyl substituents and subject to
destabilizing syn-pentane interactions. See for example: (a) Tsuzuki, S.;
Schafer, L.; Goto, H.; Jemmis, E. D.; Hosoya, H.; Siam, K.; Tanabe, K.;
Osawa, F. J. Am. Chem. Soc. 1991, 113, 4665. (b) Faˇrcas¸iu, D.; Walter,
P.; Sheils, K. J. Comput. Chem. 1989, 10, 520. (c) Pe´rez, J. J.; Villar, H.
O.; Arteca, G. A. J. Phys. Chem. 1994, 98, 2318. (d) Flory, P. J. Statistical
Mechanics of Chain Molecules; J. Wiley & Sons: New York, 1969.
1
syn-anti/syn > 8:1 by 400 MHz H NMR of the homologated
enoate46). Further manipulation as for 32 gave the meso-diol
derivative 35.52
The 13C chemical shifts of C4, C6, and C8 of several enoates
containing syn- and anti-deoxypropionate triads revealed inter-
esting correlations (Table 1 and Figure 3). Thus, within a given
pair of triads, the chemical shift value of C4 in the syn isomer
was at higher field compared to C4 in the anti isomer (Table 1,
entries 1-4). The reverse trend was observed for C6 of the syn
isomer compared to that of the anti isomer. Furthermore, within
a single syn-dimethyl triad, the C4 chemical shift value of the
(51) Compound 8 was also transformed to the corresponding meso-1,9-
dimethoxymethyl-3,5,7-trimethyl-1,9-nonane diol 34, [R]D 0 (c 0.48,
CHCl3), as also corroborated by 13C,1H NMR. Chiral GC analysis indicated
a diastereomeric purity >90%.
(52) It was not possible to obtain diastereomeric syn/anti ratios by chiral GC or
LC for intermediates 32 and 33. Transformation to the meso-hydrocarbons
34 and 35, respectively, and analysis of crude products by chiral GC
indicated a diastereomeric purity >80%.
9
J. AM. CHEM. SOC. VOL. 125, NO. 45, 2003 13789

A R T I C L E S
Hanessian et al.
Scheme 5 a
a Reagents and conditions: (a) Dibal-H, PhMe, -78 °C, (90%); (b) (COCl)2, DMSO, NEt3, CH2Cl2, -78 °C; (c) PPh3CHCO2t-Bu, CH2Cl2, (85% for two
steps); (d) MeLi‚LiBr, CuI, TMSCl, THF, -78 °C, (91%). For 32 to 33: (e) LiAlH4, THF, 0 °C, (92%); repeat b and c (93% for two steps); repeat d (93%).
For 33 to 35: (f) H2, Pd/C 10%, MeOH (99%) (g) MsCl, NEt3, DMAP, CH2Cl2; repeat e; (h) MOMCl, Hunig’s base, CH2Cl2 (84% for three steps). For 32
to 34: step e (92%); step h (93%); step f (quant); step g (71%); repeat e (70%). For 9 to 34: (i) TBAF, THF, rt; steps h and f (86% for three steps); steps
g and e (85% for two steps).
Table 1: Comparison of Selected 13C NMR Data of Syn and Anti
Triads
backbone of several acyclic structures containing syn-1,3-
dimethylpentane units, including pectinatone,16 bourgeanic
acid,59 and TMC-15118 from their X-ray coordinates. The
diamond lattice was originally used in the context of macrolide
conformational analysis.61 More recently Kishi and co-workers
used it to rationalize the conformations of C-glycosides62a and
complex natural products.62b Other applications to the study of
conformations of subunits in natural products have also been
reported.63
The quasi perfect congruence of the X-ray structures on a
diamond lattice exemplified by pectinatone (Figure 4A) en-
couraged us to use it as a visual aid to rationalize the ob-
served prevalence of syn-1,3-dimethyl orientations after each
1
cuprate addition. The 600 MHz H NMR spectrum of enoate
a Data were recorded on a Bruker DMX600 at 303 K in CD2Cl2 calibrated
at 53.8 ppm. b Chemical shifts were assigned on the basis of HMQC
experiments. c Data from a 2:1 mixture of syn/syn-10 and anti/syn-10 by
cuprate addition to 7 at -30 °C.
7 showed unusually well-resolved individual signals for the
methine and methylene protons within the triad, indicating
the prevalence of a time-averaged preferred conformer in
which the folding of the backbone was very similar to that of
(-)-pectinatone in the crystal structure. The 3J coupling
constants determined by homodecoupling experiments corre-
sponding to a conformation that is “anchored” by the O-BOM
substituent54a are listed in Figure 4B. The same trend was
observed in the case of 10 harboring a C5-C9 syn/syn-trimethyl
motif, which closely simulates the pectinatone backbone
conformation (Figure 4C). Low-energy conformations for 7 and
10 in accord with the NMR-derived results were also suggested
by MM3 studies.64
biosynthesis58 of metabolites in which stereoregular single,
double, or triple syn-1,3-dimethyldeoxypropionate triads are
created.54a This preference is nicely corroborated in the X-ray
crystal structures of (3S,5R,7R)-2,3,5-trimethyl-2,7-octanediol54b
and of acyclic natural products such as pectinatone,16 bourgeanic
acid,59 and TMC-151,18 all of which harbor syn-related 1,3-
deoxypropionate subunits, yet they adopt conformations that are
devoid of syn-pentane interactions.
In considering the synthesis of syn-deoxypropionate units by
an iterative addition of lithium dimethylcuprate to a growing
chain of δ-methyl-R,â-unsaturated esters, we relied on the basic
notion that transition-state conformations leading to intermedi-
ates in which syn-pentane interactions are minimized or avoided
would be favored. We have used a virtual diamond lattice60 as
a hypothetical template upon which we superimposed the carbon
(61) (a) Egan, R. S.; Perun, T. J.; Martin, J. R.; Mitscher, L. A. Tetrahedron
1973, 23, 2525. (b) Perun, T. J.; Egan, R. S. Tetrahedron Lett. 1969, 387.
(c) Celmer, W. D. Symposium on Antibiotics; Ste. Marguerite, Que´bec,
Canada, March 1-3, 1971; Butterworths: London, 1971; pp 413-453.
(62) (a) Wei, A.; Kishi, Y. J. Org. Chem. 1994, 59, 88 and preceding papers.
(b) Zheng, W.; DeMattei, J. A.; Wu, J.-P.; Duan, J. J.-W.; Cook, L. R.;
Oinuma, H.; Kishi, Y. J. Am. Chem. Soc. 1996, 118, 7946. See also (c)
Barbero, A.; Blakemore, D. C.; Fleming, I.; Wesley, R. N. J. Chem. Soc.,
Perkin Trans. 1 1997, 1329.
(63) See for example: (a) Taylor, R. E.; Zajicek, J. J. Org. Chem. 1999, 64,
7224 (epothilone); (b) Choy, N.; Shin, Y.; Nguyen, P. Q.; Curran, D. P.;
Balachandran, R.; Madiraju, C.; Day, B. W. J. Med. Chem. 2003, 46, 2847
(discodermolide).
(58) Block, M. H.; Cane, D. E. J. Org. Chem. 1988, 53, 4923.
(59) Bodo, B.; Trowitzsch-Kienast, W.; Schomburg, D. Tetrahedron Lett. 1986,
27, 847.
(60) (a) Dale, J. J. Chem. Soc. 1963, 93. (b) Dale, J. Angew. Chem., Int. Ed.
Engl. 1966, 5, 1000.
9
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Total Synthesis of (−)-Borrelidin
A R T I C L E S
Figure 3. (A) Partial HMQC of syn/syn-10 recorded on a Bruker DMX 600 in CD2Cl2 at 303 K. (B) Partial HMQC of an artificial mixture of syn/syn-10
and anti/syn-10 recorded on a Bruker AV 400 in CD2Cl2 at 293 K.
Figure 4. (A) X-ray crystal structure of (-)-pectinatone16 and superposition of the carbon backbone on a virtual diamond lattice. (B, C) Possible conformations
3
of 7 and 10 on the basis of relevant J coupling constants.46
In Figure 5, we depict the intermediates along the reaction
pathway65,66 for enoates 4 and 7 leading to their respective syn
adducts as major diastereomers. Starting with low-energy con-
formers in each case (corroborated by 1H NMR homodecoupling
experiments),46 the spatial disposition of the δ-methyl group
and the folding of the carbon backbone dictate the preferred
directions of approach of the cuprate reagent, leading to the
(64) Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440.
(66) (a) Frantz, D. E.; Singleton, D. A. J. Am. Chem. Soc. 2000, 122, 3288. (b)
Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3063. See also (c)
Bertz, S. H.; Carlin, C. M.; Deadwyler, D. A.; Murphy, M. D.; Ogle, C.
A.; Seagle, P. H. J. Am. Chem. Soc. 2002, 124, 13650. (d) Bertz, S. H.;
Chopra, A.; Eriksson, M.; Ogle, C. A.; Seagle, P. Chem. Eur. J. 1999, 5,
2680. (e) Krause, N.; Wagner, R.; Gerold, A. J. Am. Chem. Soc. 1994,
116, 6, 381. (f) Bertz, S. H.; Smith, R. A. J. Am. Chem. Soc. 1989, 111,
8276. (g) Christensen, B.; Olsson, T.; Ullenius, C. Tetrahedron, 1989, 45,
523. (h) Hallnemo, G.; Olsson, T.; Ullenius, C. J. Organomet. Chem. 1985,
282, 133. See also refs 32a,b and 65g.
(65) See for example: (a) Woodward, S. Chem. Soc. ReV. 2000, 29, 393. (b)
Canisius, J.; Gerold, A.; Krause, N. Angew. Chem., Int. Ed. 1999, 38, 1644.
(c) Nakamura, E.; Mori, S.; Morokuma, K. J. Am. Chem. Soc. 1997, 119,
4900. (d) Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11025. (e) Dorigo,
A. E.; Wanner, J.; von Rague’ Schleyer, P. Angew. Chem., Int. Ed. Engl.
1995, 34, 476. (f) Dorigo, A, E.; Morokuma, K. J. Am. Chem. Soc. 1989,
111, 6524. (g) Krauss, S. R.; Smith, S. G. J. Am. Chem. Soc. 1981, 103,
141.
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A R T I C L E S
Hanessian et al.
Figure 5. Proposed enoate/cuprate π-complexes and the corresponding â-cuprio(III) intermediates and adducts. Cuprates are shown as monomers for simplicity.
L ) TMSCl or THF, M ) Li or TMS.
formation of enoate/cuprate π-complexes66 4A and 7A (Figure
5). The complexes evolve to the respective â-cuprio(III) transient
intermediates65-67 4A′ and 7A′, which are stabilized by coor-
dination to TMSCl.67 Transfer of a methyl group and reductive
elimination of a copper species affords the respective products.68
1,5-Pentane-type interactions are minimized or avoided in 4A′
and 7A′, leading to a preponderance of C3-C5 syn and C3-C7
syn/syn adducts 5 and 8, respectively (Figure 5). Presumably,
the transition state in the third cuprate addition to 7 is largely
in favor of a conformer where the carbon backbone is already
folded in an energetically biased conformation to accommodate
the bulky cuprio(III) group (Figure 5B)46 leading to the major
syn/syn isomer 8.69,70
The better syn selectivity in the second cuprate addition in
the case of the enoate 31(>7:1) (Scheme 5) compared to 4 is
of interest. In the case of 31, the propionate triad harboring anti/
anti methyl groups flanking the O-BOM substituent acts as an
internal anchor54a,71 to bias a preferred conformation that favors
a syn approach of the cuprate. The trend for syn/syn selectivity
continues with the formation of 32 and 33 as the major products
(Scheme 5). It is important to note that the highest ratios of the
syn adducts in all cases were obtained with tert-butyl esters,
which may further contribute to the prevalence of lower energy
anchored conformations.71
of D-glyceraldehyde and L-malic acid as chiral progenitors and
their elaboration into fully functionalized subunits capitalizing
on 1,2- and 1,3-inductions in acyclic intermediates. A practical
attribute of this iterative approach, compared to others mentioned
earlier, particularly with regard to the C1-C11 acyclic substruc-
ture of borrelidin, is that it generates advanced intermediates
that also incorporate the C3 and C11 hydroxyl groups.
Inspired by nature’s preferences in conformational design,54a
we were able to devise a new stereocontrolled synthetic protocol
for the deployment of alternating 1,3-syn-disposed C-methyl
groups encompassed within the C1-C11 periphery of borrelidin.
The same subunit was also utilized in a total synthesis of
siphonarienal. The stereochemical outcome of iterative lithium
dimethylcuprate additions to a growing chain of acyclic δ-meth-
yl-R,â-unsaturated enoates has been rationalized on the basis
of preferred conformations in which nonbonded syn-pentane
interactions are minimized in the transition states. A virtual
diamond lattice was used to qualitatively visualize the backbone
1
conformation of acyclic chains and was corroborated by H
NMR homodecoupling studies.
Acknowledgment. We thank NSERCC for generous financial
assistance and for a postdoctoral fellowship to Y.Y. We are
grateful to Dr. A. Simay (Gyogyzerkutato Intezet Kft, Budapest,
Hungary), and Dr. T. Wakabayashi (Eisai Co. Ltd., Tsukuba,
Japan) for authentic samples of natural borrelidin.
Conclusion
A total synthesis of (-)-borrelidin, isolated as the crystalline
benzene solvate, was achieved. The strategy involved the use
Supporting Information Available: Complete experimental
procedures and NMR, X-ray, and other data (print/PDF). This
information is available free of charge via the Internet at
http://pubs.acs.org.
(67) For the effect of TMSCl. see (a) Bertz, S. H.; Miao, G.; Rossiter, B. E.;
Snyder, J. P. J. Am. Chem. Soc. 1995, 117, 11023. (b) Lipshutz, B. H.;
Dimock, S. H.; James, B. J. Am. Chem. Soc. 1993, 115, 9283. (c) Horiguchi,
Y.; Komatsu, M.; Kuwajima, I. Tetrahedron Lett. 1989, 30, 7087. See also
refs 32a,b and 66a.
(68) The corresponding ketene acetals could be isolated by avoiding any acidic
workup. See also refs 32a,b.
JA030139K
(69) As previously discussed, a fourth cuprate addition to 10 was also syn-
selective but only modestly (syn/anti 4:1), presumably due to entropic
limitations of a growing deoxypropionate chain, as observed by Hoffmann.54a
(70) Cuprate addition to the enoate derived from C5-C7 anti-deoxypropionate
(anti-7), under the same conditions led to a 2:1 mixture of isomers,
indicating the preference for a syn-disposed deoxypropionate motif such
as 7 for all-syn selectivity.
(71) (a) Cauwberghs, S.; De Clercq, P. J. Tetrahedron Lett. 1988, 29, 2943. (b)
Alder, R. W.; Allen, P. R.; Anderson, K. R.; Butts, C. P.; Khosravi, E.;
Martin, A.; Maunder, C. M.; Guy Orpen, A.; St. Pourcain, C. B. J. Chem.
Soc., Perkin Trans. 2 1998, 2083. (c) Alder, R. W.; Allen, P. R.; Hnyk,
D.; Rankin, D. W. H.; Robertson, H. E.; Smart, B. A.; Gillespie, R. J.;
Bytheway, I. J. Org. Chem. 1999, 64, 4226.
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